It is estimated that approximately 30 million Americans are infected by onychomycosis. The current method of treatment for onychomycosis is oral systemic administration of antifungal agents, which has long treatment regimen and is not very effective. Reoccurrence of the disease is not uncommon, and up to one-fourth of the patients have persistent onychomycosis. Systemic side effects due to hepatic toxicity can be severe and necessitate regular blood tests and liver function monitoring. Local topical drug delivery has fewer adverse effects than systemic administration, but has not been very successful due to the resistive nail barrier. Transungual drug delivery for nail diseases has remained a challenge to pharmaceutical scientists. The objectives of this project are (1) to mechanistically quantify the barrier properties of human nail for iontophoretic transport, (2) to overcome this barrier for topical drug delivery with iontophoresis, and (3) to develop an iontophoresis system for the treatment of nail diseases. This project includes both basic and translational research. The systematic study of the barrier properties of human nail plate will provide new understanding of transungual drug delivery. Iontophoresis will be investigated for enhancing drug uptake and transport across the nail plate. These results will then be used to develop a transungual iontophoretic drug delivery system. The methodology and theoretical frameworks developed in our last funding period for biomembrane iontophoresis will provide the necessary knowledge base and expertise for applying the iontophoretic delivery technology to transungual drug delivery and nail disease treatment. PUBLIC HEALTH RELEVANCE: Nail diseases such as onychomycosis have affected more than 30 million Americans with related healthcare spending on the diseases more than $1 billion worldwide. For example, the current method of treatment for onychomycosis is oral systemic administration of antifungal agents, which requires long treatment duration (e.g., three months), has relatively low total cure rate (less than 70%), and risks systemic side effects (e.g., hepatic toxicity). The successful development of a transungual iontophoretic system for nail disease treatment will benefit the public by improving treatment outcome and reduce healthcare cost.